Abstract Alzheimer?s disease (AD) is a devastating form of dementia with an increasing incidence due to our aging population. While the FDA-approved N-methyl-d-aspartate (NMDA) receptor drug memantine offers some modest beneficial effect, we have developed much improved novel aminoadamantane nitrates (?NitroSynapsins?) that are bifunctional NMDAR antagonists with selectivity for extra-synaptic eNMDARs relative to synaptic NMDARs. Importantly, this series of drugs has the potential to be a disease- modifying intervention for AD because the lead candidate compound (YQW-036) can reverse synaptic loss in preclinical studies in two AD transgenic animal models and dramatically improve neurobehavior on memory testing. Loss of synaptic function is associated with cognitive decline in AD. In fact, the loss of synapses is a better predictor of cognitive loss in AD than plaques or tangles (Terry, 1991; Sheng, 2012). Emerging evidence suggests that oligomers of A?42 release, via stimulation of ?7 nicotinic receptors, excessive amounts of glutamate from astrocytes, which, in turn activates eNMDARs, at least in part responsible for mediating synaptic damage. In AD, stimulation of eNMDARs also increases hyperphosphorylation of Tau, which gives rise to neurofibrillary tangles and whose deposition strongly correlates with progression of AD (Wang, 2013). Additionally, eNMDAR-mediated increases in Tau protein levels, Tau hyperphosphorylation, and caspase-3 activity in response to oligomerized A? presage the loss of synapses (Ittner, 2010; Zempel, 2010; Hyman, 2011; Jin, 2011; Morris, 2011; Sydow, 2011; D?Amelio, 2011; Talantova, 2013). Our lead NitroSynapsin can reverse these deficits, as shown in the Preliminary Studies (Talantova, 2013). Protection of the synapse may be achieved by eNMDAR antagonists sufficiently potent to protect, yet gentle enough to allow normal synaptic transmission and neurobehavioral improvement. Considering the safety profile of memantine over many years of clinical use, and the vastly improved selectivity and efficacy both in vitro and in vivo of NitroSynapsins over memantine, it seems likely that the enhanced activity of our new drugs will translate into better clinical outcomes in humans. In Phase I, we initiated clinical development of YQW-036, carrying out PK and brain uptake studies, metabolic stability studies and initial toxicity studies. Based on the successful outcome of those studies we plan to initiate IND-enabling studies under this Phase II SBIR application. Our two-year goal is to submit an IND to begin the clinical development of the first-in-class member of this novel AD-modifying class of pharmaceuticals. Phase I: 1R43AG047709-01